Diabetes is a metabolic disorder characterized by high blood sugar and its global incidence is increasing. About 90% of diabetes is type II diabetes due to excessive hepatic glucose caused by peripheral insulin resistance and high blood sugar (Pharmaceutical Development, 2003, 27: 88-91). Currently, the most commonly used drugs for type II diabetes including sulfonylurea, biguanides, α-carbon glucosidase inhibitor and insulin have good blood glucose control and lowing effect. However, they have many drug-related side effects, such as weight gain, reduced insulin secretion, hypoglycemia, and gastrointestinal adverse reactions. Therefore, there is unmet medical need to develop safer and more efficacious oral anti-diabetic drugs.
The sodium-glucose co-transporters (SGLTs) plays an important role in maintaining stable blood glucose level. SGLT-1 is mainly expressed in small intestine, kidney, heart and brain. In contrast, SGLT2's major physiological function is absorption of glucose in the small intestine. SGLT-2 is specifically distributed in the kidney proximal convoluted tubule 51 segment, and is responsible for the reabsorption of 90% glucose. The remaining 10% is carried out by SGLT-1 in the proximal convoluted tubule S3 segment. Therefore, the re-absorption of glucose can be specifically reduced by inhibiting SGLT-2's activity in the kidney resulting in excretion of excessive glucose in the urine without body weight increase or hypoglycemia. Therefore, SGLT2 inhibitor represents highly promising anti-diabetic drug (Handlon, A. L., Expert Opin. Ther. Patents 2005, 15(11):1531-1540; Am J Physiol Renal Physiol 2001, 280: 10-18).
Multiple SGLT2 inhibitors have been disclosed as published in Handlon, A. L., Expert Opin. Ther. Patents 2005, 15(11):1531-1540; Nature Reviews Drug Discovery, 2010, Vol. 9, No. 7, 551-559; WO01/27128, WO02/083066, WO03/099836, US2003/0114390, WO 04/063209, WO2005/012326, US2005/0209166. The FDA approved SGLT2 inhibitors include Jansen's Canagliflozin (approved on Mar. 29, 2013), AstraZeneca and BMS's Dapagliflozin (approved on Jan. 8, 2014), Boehringer Ingelheim's Empagliflozin (approved by CHMP on Mar. 21, 2014).